Renal dysfunction and podocyturia in pre-eclampsia may be explained by increased urinary VEGF.

BACKGROUND: Pre-eclampsia has a major impact on renal function as shown by the development of proteinuria and podocyturia. How the systemic, soluble Fms-like tyrosine kinase-1 (sFlt-1)-driven inhibition of vascular endothelial growth factor (VEGF) activity detected in pre-eclampsia directly affects renal function remains unknown. The aim of the study was to clarify whether a non-canonical, renal-centred escape from VEGF inhibition in the case of pre-eclamptic pregnancy might have a direct impact on renal function. METHODS: We evaluated plasma and urinary VEGF and placental growth factor (PlGF), plasma sFlt-1 and carbonic anhydrase IX (CAIX), albuminuria and podocyturia in 18 women with uncomplicated pregnancy, 21 with pre-eclampsia and 18 non-pregnant. The three groups were matched for age and the pregnant groups also for gestational age at enrolment. RESULTS: Plasma VEGF was reduced in uncomplicated (P = 0.001) and pre-eclamptic (P = 0.0003) pregnancies when compared with controls. In uncomplicated pregnancy, the dysfunction was balanced by an increase (P = 0.009) of plasma PlGF. Increased (P = 0.0001) plasma CAIX in pre-eclampsia was in line with hypoxia. Pre-eclampsia resulted in a paradoxical increase (P = 0.0004) of urinary excretion of VEGF. Urinary concentrations of VEGF and podocytes were correlated to each other (r2 = 0.48, P < 0.0005) but also to plasma sFlt-1 (r2 = 0.56, P < 0.0001 and r2 = 0.23, P = 0.03, respectively). CONCLUSIONS: In the case of pre-eclampsia, the systemic VEGF inhibition leads the kidney, possibly the podocyte, to increase the VEGF synthesis. The mechanisms leading to local VEGF overproduction or the overproduced VEGF itself are reasonably involved in the pathogenesis of podocyturia and, as a consequence, renal dysfunction in pre-eclampsia.

Normal sperm parameters per se do not reliably account for fertility: A case-control study in the real-life setting.

A proportion of men are infertile despite having normal medical history/physical examination and normal semen analysis. We aimed to assess whether normal sperm parameters per se account for male factor fertility. 1,957 infertile men were compared with 103 age-comparable fertile controls. Semen analysis was based on 2010 World Health Organization reference criteria. Of all, 12.1% of infertile men and 40.8% of fertile men presented with normal sperm parameters. Among fertile men, 36.9% had isolated sperm abnormalities and 22.3% men showed two or more concomitant sperm abnormalities. Serum total testosterone was higher in infertile men with normal sperm parameters compared to those with ≥2 sperm abnormalities or azoospermia, but similar to those with isolated sperm abnormalities (p ≤ .001). Circulating hormones were similar among sperm parameters groups in fertile men. At multivariable analyses, testicular volume (OR 1.12, p ≤ .001) and FSH (OR 0.8, p ≤ .001) were associated with normal sperm parameters. Overall, the longer the infertility period, the greater the number of sperm parameters abnormalities (p < .01). In conclusion, we found that 12% of infertile men and only 41% of fertile men present with normal sperm parameters. Normal sperm parameters per se do not reliably account for fertility in the real-life setting.

A Pictorial Ultrasound Essay of Gestational Trophoblastic Disease.

Gestational trophoblastic disease (GTD) includes a wide variety of clinical and histopathologic entities that require prompt identification and definition by the integration of clinical, laboratory, and imaging data. Recently, the role of grayscale ultrasound and spectral and power/color Doppler techniques has become pivotal in the diagnosis, staging, and management of GTD, thanks to both technical improvements and the growing expertise of dedicated operators. The aim of this essay is to summarize the most recent data on the ultrasound and Doppler findings of GTD and to provide a pictorial overview, including useful prognostic and therapeutic implications for clinical practice.

Prenatal Diagnosis of Twin Pregnancies with Complete Hydatidiform Mole and Coexistent Normal Fetus: A Series of 13 Cases.

AIM: The study aimed to describe prenatal diagnosis and the outcome of complete hydatidiform mole and coexistent normal fetus (CHMCF). METHODS: This was a retrospective case series of 13 patients with CHMCF. Prenatal diagnosis, outcome and development of gestational trophoblastic neoplasia (GTN) were reviewed. RESULTS: Ultrasound diagnosis was carried out in 12 of 13 cases at 17 ± 2.7 weeks of gestation (mean ± SD). Six patients showed abnormalities suggestive of subchorionic hematoma on first trimester ultrasonography (US). Prenatal invasive procedures were performed in 8 of 13 cases (62%). Two women decided to terminate their pregnancies. Four ended in late miscarriages (36%, 4 of 11) between 13 and 21 weeks, and early neonatal death occurred in 1 case (9%, 1 of 11); 5 women delivered a live baby with a mean gestational age of 31 weeks (range 26-37 weeks) with an overall neonatal survival of 45% (5 of 11). GTN occurred in 31% of cases (4 of 13). CONCLUSIONS: The first trimester US features of CHMCF are not well-documented. Our series showed that abnormalities of CHMCF could be misdiagnosed as subchorionic hematoma in the early first trimester. When CHMCF is confirmed by expert US, prenatal invasive procedures should be carefully evaluated depending on the associated US findings and exhaustive counseling should be performed.

HIF1A and MIF as potential predictive mRNA biomarkers of pre-eclampsia: a longitudinal prospective study in high risk population.

BACKGROUND: Pre-eclampsia (PE) is a hypertensive multisystem disorder, causing significant fetal-maternal mortality and morbidity worldwide. This study aims to define possible longitudinal predictive mRNA markers involved in the main pathogenic pathways of PE: inflammation [macrophage migration inhibitory factor (MIF)], hypoxia and oxidative stress [hypoxia inducible factor 1-α subunit (HIF1A) and ß-site APP-cleaving enzyme-2 (BACE2)] and endothelial dysfunction [endoglin (ENG), fms-related tyrosine kinase-1 (FLT1) and vascular endothelial growth factor (VEGF)]. METHODS: Peripheral blood was collected from 33 singleton pregnancies characterized by a high cardiovascular profile risk sampled consecutively at 6-16; 17-23; 24-30; 31-34; ≥35 weeks followed by the Obstetrics and Gynecology Unit of the San Raffaele Hospital in Milan. A real-time quantitative PCR reaction was performed on plasma RNA. RESULTS: Of the 33 women enrolled, nine developed PE. Until 23 weeks HIF1A was significantly higher in women who later developed PE compared to women who did not (p=0.049 and p=0.012 in the first and second blood collection). In the third time interval MIF (p=0.0005), FLT1 (p=0.024), ENG (p=0.0034) and BACE2 (p=0.044) appeared to be significantly increased while HIF1A was elevated even from 24 week onwards but not reaching the statistical significance. In the fourth time interval ENG mRNA still remained increased (p=0.037). CONCLUSIONS: HIF1A, marker of hypoxia and oxidative stress, and MIF, marker of inflammation, seemed to be the most promising RNA markers, suggesting that hypoxia, principally, and inflammation may play an important role in PE pathogenesis.

Weekly Paclitaxel for Pregnancy Associated Breast Cancer.

BACKGROUND: Pregnancy associated breast cancer is the most common cancer diagnosed during pregnancy. When chemotherapy is indicated, although it is more common to use anthracycline-based chemotherapy as a first treatment, we suggest weekly paclitaxel as a valid alternative both in the adjuvant and neoadjuvant setting, as this allows for weekly assessment of maternal-fetal well-being and a quicker maternal and fetal bone marrow recovery in cases of unexpected preterm delivery. PATIENTS AND METHODS: We present a case series of pregnant breast cancer patients treated with weekly paclitaxel between 2016 and 2022. Patient demographics and tumor characteristics, data on management, delivery, and maternal-neonatal outcomes were extrapolated from institutional electronic databases. RESULTS: Eighteen patients underwent weekly paclitaxel for breast cancer during pregnancy (PrBC); 17 were primary diagnoses and 1 was a recurrence. None of the patients had severe adverse reactions to CT. Two cases of preterm prelabour rupture of membranes were reported while in 1 case treatment was stopped due to threatened preterm birth. Two babies were born large for gestational age, 2 were small for gestational age and 2 babies were growth restricted at birth. At a mean follow up of 42.9 months, 1 patient died, 1 patient was diagnosed with disease recurrence and another patient was diagnosed with disease progression. CONCLUSION: Weekly paclitaxel can be safely administered during pregnancy and should be included in the current therapeutic options for PrBC.

Prenatal sonographic monitoring of idiopathic megacystis.

This case report is of a female fetus diagnosed with severe idiopathic megacystis at 21 weeks of pregnancy. Sonographic monitoring demonstrated normal amniotic fluid volume and renal structures, absence of hydronephrosis, ureteral dilation, and associated abnormalities. Conservative management was chosen with postnatal confirmation of diagnosis. The neonate presented seizures, and subsequent magnetic resonance imaging demonstrated transverse sinus thrombosis with adjacent ischemic damage. At present, the infant is 2 years old, and she is thriving normally and maintains urinary continence with spontaneous voidings.

Effects of flexible sacrum position at birth on maternal and neonatal outcomes: A retrospective cohort study.

OBJECTIVE: To examine the differences in both maternal and neonatal outcomes between flexible and non-flexible sacrum positions at birth. METHODS: A descriptive, cross-sectional, retrospective study was carried out on a sample of low-risk pregnant women. Univariate and multivariate logistic regressions and multivariate linear regressions were conducted to estimate the association between our discrete or continuous variables of interest. Maternal outcomes were perineal tear, maternal blood loss, second stage length; neonatal outcomes were Apgar scores and neonatal asphyxia. Results were adjusted for maternal age, neonatal birth weight, and epidural analgesia. RESULTS: We considered for final analysis 2198 women. In primiparous women, women giving birth in the all-fours position were significantly more likely to have an intact perineum (P = 0.011) and a shorter length of the second stage of labor (P = 0.022). Maternal age (P = 0.005) and neonatal weight (P = 0.013) significantly increased perineal tearing; maternal age (P = 0.004) and neonatal birth weight (P < 0.001) were significantly associated with a higher amount of blood loss. Maternal age (P = 0.002) and neonatal weight (P < 0.001) significantly increased the length of the second stage of labor. For multiparous women, the side-lying position was significantly correlated with an intact perineum (P = 0.031); maternal age and intact perineum were statistically inversely associated. Epidural analgesia significantly increased the length of the second stage of labor in both nulliparous (P < 0.001) and pluriparous women (P < 0.001). No significant differences were found in neonatal outcomes. CONCLUSION: Women with a low-risk labor should be free to choose their birth position as flexible sacrum positions are shown to increase maternal well-being and do not affect neonatal health.

Early increase in circulating carbonic anhydrase IX: A potential new predictive biomarker of preeclampsia.

Preeclampsia (PE) is a severe complication of pregnancy. The identification of a reliable predictive biomarker could help in setting up a specific preventive strategy. To this aim, we studied carbonic anhydrase IX (CAIX) as a marker of hypoxia (a pathway involved in PE pathogenesis) and compared the diagnostic accuracy of CAIX to that of the validated biomarker sFlt1/PlGF ratio. Fifteen women with overt PE and 38 women at a risk of developing PE, sampled at different time intervals during gestation (a total of 82 plasma samples collected), were enrolled and underwent the CAIX measurement. CAIX levels significantly increased (p < .001) before the onset of the disease in women (25% of the total number) who later on developed PE when compared to women who did not, starting from 28th gestational week. The best CAIX cut-off of 68.268 pg/mL yielded a sensitivity of 100%, a specificity of 81.82%, and an AUC value of .9221. In our pilot study, when compared to the sFlt1/PlGF ratio, CAIX performed better in predicting PE before the clinical onset. Furthermore when implemented as CAIX/PlGF ratio, showed up to be comparable in the identification of women with overt early PE. In conclusion, CAIX could represent an effective predictive biomarker of PE, and larger studies are mandatory to validate this finding.

Weekly Paclitaxel Administered During a Twin Pregnancy for Recurrent Breast Cancer: Case Report and Review of the Literature.

Although cancer treatment during single pregnancy has been standardized, how to manage cancer diagnosed during a multiple gestation is still unclear. Chemotherapy during pregnancy has shown to be safe, however, there are reports of increased risks of fetal complications such as intrauterine growth restriction and preterm birth. Also, how to best adjust this to the pharmacokinetic characteristics of a twin gestation has yet to be fully investigated. We report the case of an IVF twin pregnancy with a diagnosis of breast cancer recurrence shortly after conception, and how the pregnancy was managed to obtain optimal obstetric, maternal/oncological, and fetal outcomes.

Meningiomas in Gynecology and Reproduction: an Updated Overview for Clinical Practice.

There is various evidence to suggest a relationship between female hormones and meningiomas; as clinicians, we often come to face challenging situations involving female patients diagnosed with meningiomas during the post-pubertal phases of their life. We aimed to review the specific circumstances (pregnancy, postpartum, hormonal contraception and hormone replacement therapy, gender-affirming hormonal treatment) clinicians might come to face during their daily clinical practice, given the absence of available guidelines. We therefore conducted a narrative review on articles found in PubMed and Embase databases using appropriate keywords. Ninety-six relevant articles were included. The available evidence on managing meningiomas in post-pubertal women often implies personal strategies, highlighting the lack of a unified approach. The knowledge of the biological links between female hormones and meningiomas is fundamental to correctly counsel patients in various life phases. Prospective randomized studies are required to improve available guidelines on how to best manage meningiomas in female post-pubertal patients.

A narrative review of pregnancy after malignancies in young women that don't originate in the female genital organs or in the breast.

While cancer during pregnancy and its treatment has grown to be a popular topic in recent years, little is known on how to advise patients looking to conceive or conceiving after cancer treatment. The aim of this paper is to review the available literature on the impact of pregnancy on survivors of the most common childhood cancers, brain cancer, haematological malignancies, thyroid cancer, melanomas and sarcomas. Its main objective is to be a source of information for clinicians looking to counsel patients in these delicate moments exploiting all the available literature, albeit scarce. Given the available literature, we conclude that the presence of a multidisciplinary team is of great importance in supporting the patient and her loved ones when facing pregnancy with a previous cancer diagnosis.

Testicular volume in infertile versus fertile white-European men: a case-control investigation in the real-life setting.

Testicular volume (TV) is considered a good clinical marker of hormonal and spermatogenic function. Accurate reference values for TV measures in infertile and fertile men are lacking. We aimed to assess references values for TV in white-European infertile men and fertile controls. We analyzed clinical and laboratory data from 1940 (95.0%) infertile men and 102 (5.0%) fertile controls. Groups were matched by age using propensity score weighting. TV was assessed using a Prader orchidometer (PO). Circulating hormones and semen parameters were investigated in every male. Descriptive statistics, Spearman's correlation, and logistic regression models tested potential associations between PO-estimated TV values and clinical variables. Receiver operating characteristic (ROC) curves were used to find TV value cutoffs for oligoasthenoteratozoospermia (OAT) and nonobstructive azoospermia (NOA) status in infertile men. The median testicular volume was smaller in infertile than that of fertile men (15.0 ml vs 22.5 ml; P < 0.001). TV positively correlated with total testosterone, sperm concentration, and progressive sperm motility (all P ≤ 0.001) in infertile men. At multivariable logistic regression analysis, infertile status (P < 0.001) and the presence of left varicocele (P < 0.001) were associated with TV < 15 ml. Testicular volume thresholds of 15 ml and 12 ml had a good predictive ability for detecting OAT and NOA status, respectively. In conclusion, infertile men have smaller testicular volume than fertile controls. TV positively correlated with total testosterone, sperm concentration, and progressive motility in infertile men, which was not the case in the age-matched fertile counterparts.

Infertile Men Have Higher Prostate-specific Antigen Values than Fertile Individuals of Comparable Age.

BACKGROUND: Infertile men are at greater risk for oncological and nononcological chronic disease than fertile individuals. OBJECTIVE: To investigate prostate-specific antigen (PSA) values in men presenting for primary couple's infertility compared with a cohort of fertile individuals, according to the recommendation of the European Association of Urology guidelines that a first PSA assessment should be done at 40-45 yr of age. DESIGN, SETTING, AND PARTICIPANTS: This is a cross-sectional study. Data from 956 (90%) infertile men and 102 (9.6%) fertile participants were analysed. Circulating hormones, total PSA, and semen parameters were investigated in every man. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics, local polynomial smoothing, and linear regression models were used to test potential associations with PSA levels. RESULTS AND LIMITATIONS: Overall, PSA >1 ng/ml was found in 318 (30%) men. Serum PSA was higher (p = 0.02), while serum testosterone (p < 0.01) was lower in infertile than in fertile men. In participants younger than 40 yr, 176 (27%) men had PSA >1 ng/ml; of them, a greater proportion were infertile (28% infertile vs 17% fertile, p = 0.03). At multivariable linear regression analysis, infertile status (coefficient 0.21; 95% confidence interval 0.02-0.39) was associated with higher PSA values, after adjusting for age and serum testosterone level. This was a single-centre study, raising the possibility of selection biases. CONCLUSIONS: Infertile men have higher PSA values than fertile individuals. Of all, almost one out of three primary infertile men younger than 40 yr has a first total PSA value of >1 ng/ml. PATIENT SUMMARY: In this study, we observed that (1) infertile men have higher prostate-specific antigen (PSA) values than fertile individuals and (2) a greater proportion of infertile men younger than 40 yr had total PSA >1 ng/ml at the first assessment. These data might be relevant to study the potential clinical impact of more rigorous screening in primary infertile men.

Mode of birth in women with low-lying placenta: protocol for a prospective multicentre 1:3 matched case-control study in Italy (the MODEL-PLACENTA study).

INTRODUCTION: The term placenta praevia defines a placenta that lies over the internal os, whereas the term low-lying placenta identifies a placenta that is partially implanted in the lower uterine segment with the inferior placental edge located at 1-20 mm from the internal cervical os (internal-os-distance). The most appropriate mode of birth in women with low-lying placenta is still controversial, with the majority of them undergoing caesarean section. The current project aims to evaluate the rate of vaginal birth and caesarean section in labour due to bleeding by offering a trial of labour to all women with an internal-os-distance >5 mm as assessed by transvaginal sonography in the late third trimester. METHODS AND ANALYSIS: The MODEL-PLACENTA is a prospective, multicentre, 1:3 matched case-control study involving 17 Maternity Units across Lombardy and Emilia-Romagna regions, Italy. The study includes women with a placenta located in the lower uterine segment at the second trimester scan. Women with a normally located placenta will be enrolled as controls. A sample size of 30 women with an internal-os-distance >5 mm at the late third trimester scan is needed at each participating Unit. Since the incidence of low-lying placenta decreases from 2% in the second trimester to 0.4% at the end of pregnancy, 150 women should be recruited at each centre at the second trimester scan. A vaginal birth rate ≥60% in women with an internal-os-distance >5 mm will be considered appropriate to start routinely admitting to labour these women. ETHICS AND DISSEMINATION: Ethical approval for the study was given by the Brianza Ethics Committee (No 3157, 2019). Written informed consent will be obtained from study participants. Results will be disseminated by publication in peer-reviewed journals and presentation in international conferences. TRIAL REGISTRATION NUMBER: NCT04827433 (pre-results stage).

Carboplatin Use in Pregnancy for Stage IB3 Cervical Cancer: Case Report and Review of the Literature.

Locally advanced stage cervical cancer diagnosed during pregnancy is a clinical challenge and requires skill in balancing maternal management, fetal care, and oncological treatment. Cisplatin has been routinely used as a first line agent for neoadjuvant chemotherapy in this situation, even though it has also recently been associated with fetal hearing loss. We report a case of stage IB3 cervical cancer diagnosed at 17 gestational weeks successfully treated with neoadjuvant chemotherapy using carboplatin and paclitaxel during pregnancy. Carboplatin is a valid alternative to cisplatin for advanced stage cervical carcinoma in a pregnant patient, in particular in view of the neonatal complications (primarily ototoxicity) that are associated with in utero cisplatin exposure.

Maternal Arsenic Exposure and Gestational Diabetes: A Systematic Review and Meta-Analysis.

Gestational diabetes mellitus (GDM) is a metabolic complication associated with adverse outcomes for mother and fetus. Arsenic (As) exposure has been suggested as a possible risk factor for its development. The aim of this meta-analysis was to provide a comprehensive overview of published evidence on the association between As and GDM. The systematic search from PubMed, MEDLINE, and Scopus was limited to full-length manuscripts published in peer-reviewed journals up to April 2020, identifying fifty articles. Ten studies met the inclusion criteria, nine for quantitative synthesis with a total of n = 1984 GDM cases. The overall pooled risk was 1.56 (95% Confidence Interval - CI = 1.23, 1.99) with moderate heterogeneity (χ2 = 21.95; I2% = 64). Several differences among the included studies that may account for heterogeneity were investigated. Stratification for exposure indicator confirmed a positive association for studies assessing urine As. A slightly higher risk was detected pooling studies based in Asia rather than in North America. Stratification for GDM diagnostic criteria showed higher risks when diagnosis was made according to the Canadian Diabetes Association (CDA-SOGC) or World Health Organization (WHO) criteria, whereas a lower risk was observed when adopting the American Diabetes Association (ADA) criteria. These results provide additional evidence for a possible association between As exposure and GDM, although the data need to be interpreted with caution due to heterogeneity.

Ultrasound imaging after evacuation as an adjunct to beta-hCG monitoring in posthydatidiform molar gestational trophoblastic neoplasia.

OBJECTIVE: The purpose of this study was to identify prognostic factors associated with development of gestational trophoblastic neoplasia (GTN) after hydatidiform mole (HM). STUDY DESIGN: A retrospective analysis of 189 patients with HM was performed. We recorded features such as maternal age, HM history, blood group, gestational age, uterine volume at evacuation, presence of theca lutein cysts, vaginal bleeding, and transvaginal ultrasonography with color Doppler imaging. We considered risk predictors to be the presence of nodules and hypervascularization within the myometrium or endometrium (positive ultrasound imaging). An univariate and multivariate analysis, with the COX nominal logistic model, was performed. RESULTS: Fourteen patients experienced GTN (7.4%). After univariate analysis, uterine size (P = .0139) and positive ultrasound results (P < .0001) were associated significantly with GTN development. At multivariate analysis, only positive ultrasound results maintained significance (likelihood ratio test: chi(2) = 0.0000). CONCLUSION: The risk of GTN is increased in patients with uterine involvement that is assessed by ultrasound imaging. None of the other prognostic factors that were evaluated was predictive of GTN development.

Early diagnosis, follow-up, and prenatal treatment of a case of TRAP sequence occurring in a dichorionic triamniotic triplet pregnancy.

We are reporting a case of twin reversed arterial perfusion (TRAP) sequence occurring in a dichorionic triamniotic triplet pregnancy with successful percutaneous prenatal treatment and excellent neonatal outcome. TRAP sequence was diagnosed at 11 weeks in a spontaneous dichorionic-triamniotic triplet. Sonographic assessment showed persistent arterial flow and development of hydrops in the acardiac twin. Percutaneous cord interstitial laser coagulation was performed, and the co-twin subsequently developed growth restriction. The 9-month-old twins have a normal developmental course. This report confirms that fetal intervention is indicated in cases of TRAP sequence in which the acardiac twin presents a significant enlargement on follow-up sonographic examinations.

Prenatal diagnosis by 3D ultrasound and MRI of an unusual malformation of cortical development with brain-in-brain appearance.

A 31-year-old pregnant woman was referred for isolated mild ventriculomegaly and failure to visualize the left lateral ventricle's anterior horn on second trimester sonography (US). Three-dimensional US suspected a frontal lesion deviating the midline. MRI revealed a mass compressing the ventricle. Follow-up MRI described a "brain-in-brain" malformation: infolded microgyric cortex and white matter in frontal lobe extending to frontal horn and midline, irrorated by hypertophic Heubner artery. Conservative approach was chosen. Neurodevelopment at 1 year is normal.